Skin-care preparations containing mupirocin and betamethasone dipropionate

ABSTRACT

The present invention relates to a topical skin-care preparation in the form of an ointment containing mupirocin and betamethasone dipropionate as active principles and a carrier formulated with all or some of the following components: hydrogenated castor oil, polyethylene glycols and preservatives. The inventive preparation is advantageous over prior art compositions in that it has a specific therapeutic effect on primary and secondary skin infections, such as relief of pruritic inflammatory manifestations of dermatosis, a wide range of activity against the majority of bacterial species involved in skin infections, and a high level of activity against  Staphylococcus  and  Streptococcus,  including multi-resistant strains. In addition, the therapeutic effect of the preparation is not affected by the size of the inoculum and the preparation has no sensitization potential, thereby providing the product with an excellent safety profile for use by the patient. Moreover, the preparation can counteract the possible secondary effects of one of the components with the effect of another.

FIELD OF THE INVENTION

The present invention relates to a topical skin-care preparation in theform of an ointment containing mupirocin and betamethasone dipropionateas active principles and a carrier formulated with all or some of thefollowing components: hydrogenated castor oil, polyethylene glycols andpreservatives.

BACKGROUND OF THE INVENTION

The therapeutic applications of the product to be patented, taking intoaccount the combination of both active principles, are the following:

In primary and secondary skin infections, such as:

a) Impetigo

b) Hypoderma

c) Cellulitis

d) Balanitis

e) Folliculitis

f) Furunculosis

g) Styme

h) Abrasions

i) Infected burnings

j) Infected psoriases

k) Infected ulcers

For the relief of inflammatory manifestations of hyperkeratosicdermatoses and dry dermatoses which respond to corticosteroids such aspsoriasis, chronic atopic dermatitis, neurodermatitis (chronic simplelichen), lichen planus, eczema (including nummular eczema, hand eczema,dermatitis eczematosa), dyshidrosis (pompholyx), scalp seborrheicdermatitis, ichthyosis vulgaris and other ichthyosical affections.

It is possible to find in the state of the art that mupirocin is a broadspectrum antibiotic, obtained by fermentation from Pseudomonasfluorescens and that betamethasone dipropionate is a syntheticfluorinated corticosteroid.

Betamethasone dipropionate is a synthetic corticosteroid fordermatological topical use which at pharmacological doses displaysanti-inflammatory, antipruritic and vasoconstricting effects. This isdue to the lysosomal membrane stabilization, which precludesextracellular release of inflammation mediators. Also betamethasonedipropionate on skin has an inhibition effect on polyamine synthesis, anactive component in cell proliferation and growth. It also producesimmune system suppression, keratinocyte DNA synthesis inhibition andvasoconstriction. With this, the role of betamethasone dipropionate inthe efficiency, efficacy, safety and absorption ability to the actionsite is demonstrated.

Mupirocin inhibits in vivo synthesis of bacterial proteins, preventingisoleucine (Ile) incorporation to the protein by reversible and specificbinding to bacterial isoleucil transfer-RNA synthase (FIG. 4). Due tothis action mechanism, mupirocin shows no cross-resistance with otherantibiotics such as: chloramphenicol, erythromycin, fusidic acid,gentamycin, lincomycin, methicillin, neomycin, novobiocin, penicillin,streptomycin, and tetracycline.

Mupirocin is an antibacterial agent that inhibits Gram-positive andGram-negative bacteria growth. Bacteria susceptible to in vitromupirocin action include aerobic strains of Staphylococcus aureus(including methicillin-resistant strains and beta lactamase-producingstrains), Staphylococcus epidermidis, other staphylococci such aspositive or negative α-streptococcus hemolytic coagulase, hemolytic betastreptococcus, streptococcus group A (including S. pyogenes), other betastreptococcus (including S. agalactiae), streptococcus type D (includingS. faecalis and S. faecium), streptococcus group viridians,Streptococcus pneumoniae, Corynebacterium hofmanil, Bacillus subtilis,Escherichia coli, Klebsiella pneumonia, Proteus mirabilis, Proteusvulgaris, Enterobacter cloacae, Enterobacter aerogenes, Citrobacterfreundii, Haemophilus influenzae (including beta lactamase-producingstrains), Neisseria gonorrheae (including beta lactamase-producingstrains), Neisseria meiningitidis, Brahamella catarrhalis andPasteurella multocisa, and anaerobic isolates of Peptostreotococcusanaerobius, Clostridium difficile and Clostridium sporogenes.

It is also known that PEG 40 hydrogenated castor oil is a fatty acidtriglyceride. It is a polyethylene glycol derived from hydrogenatedcastor oil with an average 40 mol of ethylene oxide.

On other hand, is it widely known that

Polyethylene glycol 600 and PEG 150 Distearate are ethylene oxide andwater polycondensation products or also known as polyethylenic glycolswith molecular weights ranging from 200 to 8000. Only one or acombination of different polyethylene glycols with different molecularweights can be used as main carriers and/or thickeners.

An anti-inflammatory mechanism is at the cell membrane level, acting intwo ways: by direct action or through lipocortin which in turn inhibitsphospholipase A2, thus blocking arachidonic acid activation andpreventing prostaglandin, thromboxane and leukotriene production andhence reducing the anti-inflammatory process.

Corticosteroid specific receptors have been identified on skin both onnormal human epidermis and in dermal fibroblasts with which itsantiproliferative effect is correlated.

Immunosupressing activity of topical corticosteroids is due to thesemolecules causing a Langerhans cell reduction, inhibiting T cellactivity by inducing apoptosis thereof and of eosinophils, as well asblocking the cell cycle.

Savant et al., conducted a study directed to determining the therapeuticefficacy and safety of mupirocin 2%/betamethasone dipropionate 0.05%ointment in the treatment of infected dermatoses. For this, differentspecialized physicians from different parts of India were invited, whoprospectively analyzed the clinical evolution of the patients enrolledin the study for a period of 7 days. The participating patients appliedthis medicament three times a day both in primary infections complicatedby some kind of dermatosis as in those secondarily infected dermatoses.A total of 251 patients and 27 physicians were included in the study;mupirocin 2%/betamethasone dipropionate 0.05% ointment showed a 94.8%efficacy on the infected dermatoses; more than 70% of these patientsdisplayed a clinical improvement after 7 days of initiating thetreatment. No adverse effects were reported during treatment. With thesedata the participant physicians concluded that mupirocin2%/betamethasone dipropionate 0.05% ointment proved to be a safe andefficient medicament for treating infected dermatoses.

OBJECTS OF THE INVENTION

One of the objects of the present invention is to make possible amedicament having specific therapeutic action against primary andsecondary skin infections as well as the relief of dermatosesinflammatory and pruritic manifestations.

Another object is to have a product that assures a broad activityspectrum against the majority of bacterial species involved in skininfections and further having a high level of activity againststaphylococcus and streptococcus, including multi-resistant strains.

Yet another object is to produce a medicament which therapeutic actionis not affected by the size of the inoculum, and further having nosensitization potential, thereby providing the product with an excellentsafety profile for use by the patient, and further having the ability tocounteract the possible secondary effects of one of the components withthe effect of another.

Still another object is to confer the active compounds a rapid and moreelevated percutaneous absorption or penetration.

Other objects and advantages of the present invention will be apparentfrom studying the following description and attached drawings, only forillustrative and no limitative purposes.

SUMMARY OF THE INVENTION

Corticosteroid percutaneous absorption is dictated by many factors, suchas epidermal barrier integrity, the use of dressings or clothing on theapplication site, etc. As all topical corticosteroids, percutaneousabsorption of betamethasone dipropionate is increased in the skin'sinflammatory processes and with the use of occlusive dressings. Onceabsorbed, said topical corticosteroids display a pharmacokinetic profilesimilar to that of systemic corticosteroids. They can bind plasmaproteins at different concentrations, are primarily metabolized in theliver and are excreted trough kidneys and bile ducts.

The extended use of topical corticosteroids in dermatology is due totheir anti-inflammatory, antiproliferative and immunosupressing effects.Steroids are somewhat hydrophobic molecules able to pass through cellmembranes by simple diffusion or through specific receptors. Themolecular mechanism involved in the anti-inflammatory action starts withits binding to cytoplasm receptors, forming a complex that is dimerizedand translocated to the nucleus and which is able to bind DNA, where itbinds glucocorticoid response elements, resulting in an increase of thetranscription genes which encode anti-inflammatory proteins, such aslipocortin 1, interleukin 10, endopeptidase antagonist and neutralreceptor.

The most important effect is at the level of inhibition of theexpression of genes related to the production of multiple inflammatoryproteins: cytokines, enzymes, adhesion molecules and receptors; thisinhibitory effect is due to the interaction of the activatedcorticosteroid receptor and a transcription factor such as kappa Bnuclear factor and protein 1/calpactin activating factor, which regulatethe expression of inflammatory genes.

With clinical studies it was demonstrated that mupirocin ointment,C-14-labeled, at the lower part of the arm of healthy male subjects,followed by occlusion for 24 hours, showed no measurable systemicabsorption. The measurable radioactivity was limited to the stratumcorneum in these subjects 72 hours after its application. Mupirocinointment showed no late hypersensitivity, contact sensitivity,phototoxicity or photocontact sensitivity, in studies conducted innormal subjects.

Also, in a study performed on 23 healthy subjects it was confirmed thatthe application of 2% mupirocin ointment on a body surface area of 400cm² once a day, reported as added urinary excretion mean correspondingto monic acid 1.25% (0.2% to 3.0%) of the total mupirocin dose applied.The urinary concentration of monic acid taken at specific intervalsduring 24 hours up to day 7 of the study ranged between <0.050 to 0.637μg/mL.

After several tests it could be determined that mupirocin hasbactericide action at the obtained concentrations in a 2% topicalformulation.

An animal model study was performed in order to demonstrate the efficacyof mupirocin when compared to systemic or topical antibiotics ofdifferent chemical nature. The murine model used consisted of surgicalwounds infected with S. aureus or S. pyogenes. The topical treatment wasapplied 4 and 10 hours post-infection and the treatment with systemicantibiotics at clinically relevant doses was administered 4, 8 and 12hours post-infection; both treatments were continued 3 times/day for 3days.

Among the results it was reported that mupirocin cream was statistically(p<0.01) more effective than mupirocin ointment in reducing the numberof bacteria present in the wounds. Mupirocin cream was similar inefficacy to flucloxacillin but statistically more effective (p<0.001)than oral erythromycin. It also showed similar efficacy to cefalexine vsS. pyogenes but higher against S. aureus (p<0.01). Mupirocin creamshowed the same efficacy as fusidic acid against S. aureus butsignificantly higher against S. pyogenes (p<0.01).

An impetigo murine model infected with S. aureus was also used in thisstudy. The treatments used included topical and systemic antibioticswithin 24 and 30 hours post-infection (as well as 36 hourspost-infection for oral antibiotics) and subsequently 3 times/day for 2days more. At the fifth day of treatment mupirocin cream wasstatistically more effective than mupirocin ointment (p<0.01) anderythromycin and cefalexine. With these data the efficacy of mupirocincream as topical antibiotic is proven in the use of bacterial skininfections such as impetigo. With this, the involvement of betamethasonedipropionate in the efficiency, safety and absorption ability to theaction site is demonstrated.

Hydrogenated castor oil is used as a cosolvent for enhancing solubilityof mupirocin. Further, at the concentration used in the formula, itconfers mildness to the product. This material when used as an excipientfor products intended to be topically applied, is relatively non toxicand non irritant such that its safeness is demonstrated in this way.

PEG 150 distearate is used as thickener agent which, by being apolyethylene glycol, shows affinity both for PEG 40 hidrogenated castoroil and polyethylene glycol 600, so there is no interaction orincompatibility of any kind with the rest of the product excipients.This material when used as excipient for products intended to betopically applied, is relatively non toxic and non irritant so itssafeness is thus demonstrated.

Polyethylene glycol 600 is used as a carrier that, by being apolyethylene glycol, shows affinity both for PEG hydrogenated castor oiland PEG 150 distearate so there is no is no interaction orincompatibility of any kind with the rest of the product excipients.This material when used as excipient for products intended to betopically applied, is relatively non toxic and non irritant so itssafeness is thus demonstrated.

For a better understanding of the invention, it follows a detaileddescription of one its embodiments, shown in the examples that forillustrative but not limitative purposes are attached to the presentdisclosure.

DETAILED DISCLOSURE OF THE INVENTION

The present preparation is a product having a broad antibacterialspectrum, with anti-inflammatory and antipruritic activity. It is aformulation that can be made by using a manufacturing process whichassures the highest product quality as a result of controls that takeplace during manufacturing and conditioning processes with a formulathat fulfills stability standards, wherein each and every ingredient isin balance.

Due to the antibacterial and anti-inflammatory residual action of thecombination of actives, the composition offers a protection protractedaction even after 24 hours of application provided that the product hasnot been intentionally or incidentally removed. This allows to considerthat with the constant use of the present invention composition, ahigher therapeutic efficacy is obtained than if the products were usedincluding the actives separately.

In the tests conducted on the product suitable composition, it could beestablished that if mupirocin concentration is substantially reduced toless than 2.0% the efficacy of the product is reduced, thus delaying thetherapeutic activity of the product by lengthening treatment time.Further, it could be confirmed that if the active concentration issubstantially increased over 5%, even when all the active is absorbedthere are no toxic effects or in very few occasions the product cancause pruritus and erythema on the patient which disappear whensuspending the medicament. There are no data which demonstrate anincrease in the product's efficiency or efficacy.

As regards to betamethasone dipropionate, it could be established thatif the concentration is substantially reduced from 0.0500% the efficacyof the product is reduced, thus delaying the therapeutic activity of theproduct by lengthening treatment time and in the worst case, no activeabsorption will be achieved and the therapeutic activity shall be null.If the active concentration is substantially increased over 0.0643%,excessive and protracted use of topical corticosteroids could suppresspituitary-suprarenal function, thus causing secondary suprarenal failurewith manifestations of hypercorticism, including Cushing's syndrome andin few occasions the product could cause in the patient a feeling ofburning, itching, irritation, dryness, folliculitis, hypertrichosis,acneiform eruptions, hypopigmentation, perioral dermatitis, allergiccontact dermatitis, skin maceration, secondary infection, skin atrophy,striae and miliaria, which disappear by gradually suspending themedicament. There are no data which demonstrate an increase in theproduct's efficiency or efficacy.

The product further has three excipients, one for attaining dissolutionof the molecule active components, other giving the product viscosityand the other being the balance carrier. These excipients are specificto achieve above all stability of the product. No other dissolvent, norno other viscosity modifier, as well as no other carrier, achievestability of the active compounds.

As dissolvent use is made of PEG 40 hydrogenated castor oil. If theconcentration is substantially reduced under 5.00% the carrierdissolution ability for solving mupirocin is reduced. If the excipientconcentration is substantially increased over 15.0%, the product is mademore expensive and PEG 40 hydrogenated castor oil function starts tomodify the product's physical characteristics rendering it harder anddifficult to apply.

As viscosity modification agent use is made of PEG 150 distearate. Ifthe concentration is substantially reduced under 10.0% the product losesviscosity thus making it too fluid and also losing its functionality andrendering its handling cumbersome by being conditioned in aluminum tubeas primary container. If the excipient concentration is substantiallyincreased over 20.0%, viscosity shall be increased to such an extentthat its conditioning in the primary container, the handling thereof andits functionality shall be highly affected until making it even moredifficult to apply and unpleasant for the patient.

Finally, the chosen carrier is polyethylene glycol 600. As thisexcipient is the balance carrier, if concentrations of the remainder ofthe formula excipients are observed, the result of the productapplication shall not be altered if used under 40.0% and above 80.0%.

For determining this standard levels, a series of tests discussed in thefollowing examples were performed.

Examples Example 1 Room Temperature Solubilities

TABLE 1 Solubility tests for product actives by mixing at 60 rpm and atroom temperature Betamethasone Condition Solvent Mupirocin dipropionateRoom Purified Water + + temperature Propyleneglycol + + ConstantPolyethylene + + Mixing glycol 600 Glycerin + + PEG 40 ++ ++Hydrogenated castor oil Mineral oil + + (+ = Insoluble; ++ = mildlysoluble; +++ = soluble; ++++ = very soluble)

Example 2 Solubilities at 60° C.

TABLE 2 Solubility tests for product actives by mixing at 60 rpm and 60°C. temperature Betamethasone Condition Solvent Mupirocin dipropionateRoom Purified Water + + temperature Propyleneglycol ++ ++++ ConstantPolyethylene +++ ++++ Mixing glycol 600 Glycerin ++ +++ PEG 40 ++++ ++++Hydrogenated castor oil Mineral oil ++ ++++ (+ = Insoluble; ++ = mildlysoluble; +++ = soluble; ++++ = very soluble)

From the solubility tests reported in Table No. 1 and 2, it is concludedthat the most suitable solvent for dissolving mupirocin andbetamethasone dipropionate is PEG 40 hydrogenated castor oil and thecondition for achieving their dissolution is by heating the solvent to60° C.

As for the ointment base determination, an ointment base having thefollowing components was tested: white petrolatum (carrier), NF 85mineral oil (texture and appearance modifier), PEG 40 hydrogenatedcastor oil (solvent), glycerin (moistener), butyl hydroxy toluene(antioxidant), methyl paraben and propyl paraben (preservatives),mupirocin and betamethasone dipropionate (active ingredients). Themanufacture process was the following: In an appropriate size vessel thewhite petrolatum, mineral oil and glycerin were placed, this mixture washeated up to a temperature of 75° C. and then the butyl hydroxy toluenewith the parabens was dissolved; separately in other suitable sizevessel the PEG 40 hydrogenated castor oil was placed, heated up to a 60°C. temperature and mupirocin and betamethasone dipropionate were solvedtherein; when both mixtures were at 60° C. they were mixed and the finalproduct was obtained after lowering the temperature with constant mixinguntil reaching ambient temperature.

Once the product was obtained three samples were analyzed, collectedfrom different parts of the vessel containing the product, by ActiveEvaluation techniques reported for each of them in the individualmonographs included in USP23 NF/21. Results are reported in Table No. 3.

TABLE 3 Results obtained after evaluating the actives for the proposedformula Evaluation Active Principle Results (%) Specification MupirocinSample 1 70.5 90.0 to 110.0% Sample 2 71.2 Sample 3 70.7 BetamethasoneSample 1 100.6 90.0 to 110.0% dipropionate Sample 2 100.2 Sample 3 100.2

The above results indicate that the product is homogeneous because ofthe uniformity of the obtained results, but it is assumed that mupirocinhas some incompatibility with some of the excipients because itsevaluation is practically 30% under the expected mean.

In order to test the possible incompatibility of mupirocin with one ofthe excipients the following tests reported in Table No. 4 wereperformed and the results are the following:

TABLE 4 Incompatibility tests and evaluation results when analyzing theproduct immediately after being prepared TESTS INGREDIENTS 1 2 3 4 5 6 7Mupirocin x x x x x x x Betamethasone x x x x x x x dip. PEG 40 x x x xx x x hydrogenated castor oil Butyl hydroxy — x x x x x x toluene Propyl— — x x x x x paraben Methyl — — — x x x x paraben Glycerin — — — — x xx Mineral oil — — — — — x x White — — — — — — x petrolatum Mupirocin98.8 99.3 98.7 98.9 99.0 98.8 69.8 evaluation Betamethasone 100.2 100.3100.2 99.8 100.2 100.4 99.3 dip. evaluation

According to the results it can be concluded that mupirocin in thepresence of white petrolatum undergoes a possible chemical degrading. Itthen followed a simple incorporation of the active in the whitepetrolatum at a temperature of 60° C. and it was seen that immediately acream color precipitate forms having a gummy appearance and hard. Withthese data it can be concluded that mupirocin is incompatible with whitepetrolatum. Therefore, this ointment base with mupirocin is discarded.

From the up to now obtained results, other ointment base wherein thereis any kind of petrolatum or any petroleum-derived hydrocarbon isproposed.

Taking the experience that mupirocin and betamethasone dipropionate aresoluble at 60° C. in PEG 40 hydrogenated castor oil and in polyethyleneglycol 600 (according to Table No. 2), a formulation having thefollowing ingredients is proposed: mupirocin and betamethasonedipropionate (active ingredients), PEG 40 hydrogenated castor oil(cosolvent), polyethylene glycol 600 (balance excipient or carrier), PEG150 distearate (thickener) and methyl paraben (preservative). Themanufacturing process was the following: In an appropriate size vesselthe polyethylene glycol 600 and PEG 40 hydrogenated castor oil wereplaced, this mixture was heated up to a temperature of 70° C. and thenthe methyl paraben, mupirocin and betamethasone dipropionate weredissolved; once all the above ingredients were dissolved, thetemperature was lowered with constant mixing until reaching 60° C.; itwas then added the PEG 150 distearate and continued mixing until themixture was homogenous; the final product was obtained after loweringthe temperature with constant mixing until reaching ambient temperature.

Once the product was obtained three samples were analyzed, collectedfrom different parts of the vessel containing the product, by ActiveEvaluation techniques reported for each of them in the individualmonographs included in USP23 NF/21. Results are reported in Table No. 5.

TABLE 5 Results obtained after evaluating the actives for the proposedformula Evaluation Active Principle Results (%) Specification MupirocinSample 1 98.7 90.0 to 110.0% Sample 2 99.1 Sample 3 99.4 BetamethasoneSample 1 99.8 90.0 to 110.0% dipropionate Sample 2 100.3 Sample 3 100.1

The product also has physical properties with suitable features for theointment pharmaceutical form (Appearance: an homogeneous, spreadablewhite color semi-solid free from foreign particles and with acharacteristic odor; pH 7.5; viscosity 80,000 cPs).

Finally, with the results obtained in Table No. 5, the obtainedformulation was subject to the accelerated stability test according toMexican Official Standard NOM-073-SSA1-1993, Medicament Stability. Theresults obtained after the three-month period of testing weresatisfactory.

After these tests and some other more the following compositionpossibilities of the product object of the present disclosure wereobtained.

TABLE 7 Ingredients and their concentrations to be protected by thepresent patent Ingredient Function Mupirocin Active Betamethasonedipropionate Active PEG 40 hydrogenated castor oil Cosolvent and anyderivative or combination of hydrogenated castor oil PEG 150 distearateand any Thickener derivative or combination of polyethylene glycolsPolyethylene glycol 600 and any Carrier derivative or combination ofpolyethylene glycols Methyl paraben and its salts, Preservative ethylparaben and its salts, propyl paraben and its salts, butyl paraben andits salts, butyl hydroxy anisole, bentonite, imidazolidinyl urea,potassium metabisulphite, potassium sorbate, propionic acid, propylgallate, sodium benzoate, sodium metabisulphite, sodium propionate,thimerosal, xylitol.

The invention has been sufficiently disclosed for a person skilled inthe art to reproduce and achieve the same results as those mentioned inthe present invention. However, any person having an average skill inthe field to which the present invention belongs can be able of makingmodifications not disclosed in the present application, however, if forthe application of these modifications to a determined composition or inthe manufacturing process thereof, the subject matter claimed in thefollowing claims is needed, said structures must be comprised within thescope of the invention.

1. Skin-care preparations containing mupirocin and betamethasonedipropionate, characterized by comprising as cosolvent PEG 40hydrogenated castor oil or any derivative or combination includinghydrogenated castor oil; as thickener PEG 150 distearate or anycombination thereof or any combination including it and as a carrierpolyethylene glycol 600 or any combination or derivative thereof. 2.Skin-care preparations containing mupirocin and betamethasonedipropionate, characterized by having the following quantitativecomposition: Ingredient Composition content Mupirocin 2.0%-5.0%Betamethasone dipropionate 0.05%-0.06% hydrogenated castor oil 5.0%-15.0% PEG 150 distearate 10.0%-20.0% Polyethylene glycol 60040.0%-80.0%